Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake

Highlights

• Neuronal stimulation in slices or in vivo transiently increases cytosolic NADH:NAD⁺

• Lactate shuttling into neurons is not required for the cytosolic NADH transients

• Stimulation increases neuronal glycolysis rather than lactate metabolism

• After stimulation, neurons are likely net exporters of lactate

Summary

Proper brain function requires a substantial energy supply, up to 20% of whole-body energy in humans, and brain activation produces large dynamic variations in energy demand. While local increases in cerebral blood flow are well known, the cellular responses to energy demand are controversial. During brain excitation, glycolysis of glucose to lactate temporarily exceeds the rate of mitochondrial fuel oxidation; although the increased energy demand occurs mainly within neurons, some have suggested this glycolysis occurs mainly in astrocytes, which then shuttle lactate to neurons as their primary fuel. Using metabolic biosensors in acute hippocampal slices and brains of awake mice, we find that neuronal metabolic responses to stimulation do not depend on astrocytic stimulation by glutamate release, nor do they require neuronal uptake of lactate; instead they reflect increased direct glucose consumption by neurons. Neuronal glycolysis temporarily outstrips oxidative metabolism, and provides a rapid response to increased energy demand.